1. Field of the Invention
This invention relates to camptothecin analogs having an E-ring ketone which inhibit the enzyme topoisomerase I and have anticancer activity. This invention is also related to the treatment of tumors in animals with camptothecin analogs
2. Background of the Invention
Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid which is known to inhibit the enzyme topoisomerase I and is a potent anti tumor agent. Camptothecin compounds have the general ring structure shown below. 
Camptothecin was isolated from the wood and bark of Camptotheca acuminata by Wall et al. (Wall et al., 1966, J. Am. Chem. Soc., 88:3888). It has been shown that if the E-ring α-hydroxy lactone functions are altered or removed, that the resulting compounds have no activity regarding topoisomerase I inhibition or inhibition of cancer cells. (Wall, Plant Antitumor Agents. V. Alkaloids with Antitumor Activity Symposiumsberichtes, pp. 77 87, 4. Internationales Symposium, Biochemie und Physiologie der Alkaloide, Halle (Saale) 25. Bis 28. June, 1969, edited by K. Mothes, K. Schreiber, and H. R. Schutte, Akademie Verlag, Berlin, 1969; and Nicholas et al, J. Med. Chem., 33, 972 (1990).)
Another process that affects all camptothecin compounds is that at an alkaline pH, as low as 7.5 or higher, the lactone-ring is readily hydrolyzed to give an E-ring opened carboxylate product. This compound is much less active in the above mentioned activities.
The cytotoxic activity of camptothecin compounds is believed to arise from the ability of these compounds to inhibit both DNA and RNA synthesis and to cause reversible fragmentation of DNA in mammalian cells. Topoisomerase I relaxes both positively and negatively supercoiled DNA and has been implicated in various DNA transactions such as replication, transcription and recombination. The enzyme mechanism is believed to involve a transient breakage of one of the two DNA strands and the formation of a reversible covalent topoisomerase I enzyme DNA complex. Camptothecin interferes with the DNA breakage reunion reaction by reversibly trapping the enzyme DNA intermediate termed the “cleavable complex”. The cleavable complex assay is a standard test for determining the cytotoxic activity of camptothecin compounds. The high levels of topoisomerase I in several types of human cancer and the low levels in correspondingly normal tissue provide the basis for tumor treatment with biologically active camptothecin analogs.
U.S. Pat. No. 4,894,456 describes methods of synthesizing camptothecin compounds which act as inhibitors of topoisomerase I and are effective in the treatment of leukemia (L 1210). U.S. Pat. No. 5,225,404 discloses methods of treating colon tumors with camptothecin compounds.
Numerous camptothecin compounds and their use as inhibitors of topoisomerase I are reported by U.S. Pat. No. 5,053,512; U.S. Pat. No. 4,981,968; U.S. Pat. No. 5,049,668; U.S. Pat. No. 5,106,742; U.S. Pat. No. 5,180,722; U.S. Pat. No. 5,244,903; U.S. Pat. No. 5,227,380; U.S. Pat. No. 5,122,606; U.S. Pat. No. 5,122,526; and U.S. Pat. No. 5,340,817.
U.S. Pat. No. 4,943,579 discloses the esterification of the hydroxyl group at the 20 position of camptothecin to form several prodrugs. This patent further discloses that the prodrugs are water soluble and are converted into the parent camptothecin compounds by hydrolysis.
Brangi et al., Cancer Research, 59, 5938 5946 Dec. 1, 1999, reports an investigation of Camptothecin resistance in cancer cells and reports the compound difluoro 10, 11 methylenedioxy 20(S) camptothecin.
A need continues to exist, however, for camptothecin analogs having improved stability under physiological conditions.